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Open Access Original investigation

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Changqing Yu12, Zhen Wang12, Yu Han12, Yukai Liu12, Wei Eric Wang12, Caiyu Chen12, Hongyong Wang12*, Pedro A Jose34 and Chunyu Zeng12*

Author Affiliations

1 Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China

2 Chongqing Institute of Cardiology, Chongqing, P.R. China

3 Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

4 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

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Cardiovascular Diabetology 2014, 13:97  doi:10.1186/1475-2840-13-97

Published: 2 June 2014

Abstract

Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin’s action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague–Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.

Keywords:
Dopamine receptor; Insulin receptor; Vascular smooth muscle cell; Proliferation; Migration; Atherosclerosis